The present invention relates to the prophylaxis or treatment of a 5-HT2C and a 5-HT6 receptor-related disease. In addition, the invention provides a pharmaceutical composition containing a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist for therapeutic use.
Serotonin (5-hydroxytryptamine or 5-HT) is a key neurotransmitter of the peripheral and central nervous system (PNS and CNS) and has been implicated in a variety of sensory, motor and behavioral functions such as regulation of eating, sleeping, body temperature, blood pressure, emotions and cognition. At least 14 distinct serotonin receptor subtypes are expressed in the mammalian PNS and CNS and have been formally classified; see Glennon, et al., Neurosci. Biobehav. Rev. 1990, 14, 35-37; and D. Hoyer, et al., Pharmacol. Rev. 1994, 46, 157-203. Serotoninergic agonists and antagonists have been suggested for the treatment of a wide range of disorders, including anxiety, depression, hypertension, migraine, obesity, drug abuse and addiction, compulsive disorders, schizophrenia, autism, neurodegenerative disorders (e.g. Alzheimer""s disease, Parkinsonism, and Huntington""s chorea), and chemotherapy-induced vomiting.
The 5-HT2 subfamily of receptors is composed of three subtypes, the 5-HT2A, 5-HT2B and 5-HT2C receptors. Serotonin 5-HT2C receptors are expressed in many brain regions and have been implicated in the regulation of food intake (Dourish, C. T. Obes. Res. 1995, 3, Suppl. 4, 449S-462S; Bickerdike, M. J., et al. Diabetes, Obes. Metab. 1999, 1, 207-214). It has been demonstrated that the non-specific 5-HT2C receptor agonist m-chlorophenylpiperazine (m-CPP), which has some preference for the 5-HT2C receptor, reduces food intake in mice that express the normal 5-HT2C receptor while the compound lacks activity in mice expressing the mutated inactive form of the 5-HT2C receptor (Tecott, L. H., et al. Nature 1995, 374, 542-546).
Moreover, it has been reported that m-CPP and the azepinoindole U-22394A, the latter recently identified to be a 5-HT2C receptor agonist (unpublished observation), reduce body weight in humans following two and nine weeks of treatment, respectively (Walsh, A. E. S., Psychopharmacology 1994, 116, 120-122; Sargent, P. A., et al. Psychopharmacology 1997, 133, 309-312 and Gallant, D. M., et al. Curr. Ther. Res. 1967, 9, 579-581).
Recently, a series of pyrrolo[3,2,1-ij]quinoline derivatives was identified to be 5-HT2C receptor agonists having selectivity over the 5-HT2A receptor (Isaac M., et al., Bioorg. Med. Chem. Lett. 2000, 10, 919-921). The compounds are said to offer a novel approach to the treatment of obesity and epilepsy.
The 5-HT2C receptor subtype has also been suggested to be involved in CNS disorders, such as depression and anxiety (Jenck, F., et al. Expert Opin. Invest. Drugs 1998, 7,1587-1599; Leysen, D. C. M. IDrugs 1999, 2, 109-120). The 5-HT2C receptor subtype has further been suggested to be involved in urinary disorders such as urinary incontinence (Leysen, D. C. M. IDrugs 1999, 2, 109-120).
Also the 5-HT6 receptor (identified in 1993-Monsma et al., Mol. Pharmacol. 1993, 43, 320-327 and Ruat, M. et al. Biochem. Biophys. Res. Commun. 1993, 193, 269-276) has been implicated in the regulation of food intake and CNS disorders.
Thus, for example, Bentley, J. C., et al., Br. J. Pharmacol. 1999, 126, 66P describes food intake reduction in rats by the administration of a 5-HT6 antagonist. Also, several antidepressants and atypical antipsychotics display high affinity for the 5-HT6 receptor which have suggested the involvement of the 5-HT6 receptor in schizophrenia (Roth et al. J. Pharmacol. Exp. Ther. 1994, 268, 1403-1410; Sleight et al. Expert Opin. Ther. Patents 1998, 8, 1217-1224; Bourson et al. Br. J. Pharm. 1998, 125, 1562-1566; Boess et al. Mol. Pharmacol. 1998, 54, 577-583; Sleight et al. Br. J. Pharmacol. 1998, 124, 556-562). In addition, the 5-HT6 receptor has been linked to generalized stress and anxiety states (Yoshioka et al. Life Sci. 1998, 17/18, 1473-1477).
According to the present invention it has now unexpectedly been found that the combined administration of a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist reduces food intake by more than the administration of either agonist or antagonist alone. Such combined administration of a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist may offer therapeutic advantages as compared to treatment with either agonist or antagonist alone.
One aspect of the present invention therefore provides a pharmaceutical composition comprising an effective amount of a combination of a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist, and optionally a pharmaceutically acceptable carrier.
Another aspect of the invention provides a method of preventing or treating a disease, in particular obesity, related to the 5-HT2C receptor and the 5-HT6 receptor, comprising administering to a human or animal subject in need thereof a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist (simultaneously or sequentially) in sufficient amounts to provide a therapeutic effect.
Still another aspect of the invention provides the use of a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist for the manufacture of a medicament for the treatment of a disease related to the 5-HT2C receptor and the 5-HT6 receptor.
Another aspect of the invention provides a process for preparing a pharmaceutical composition, wherein a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist in a combined therapeutic amount are intimately mixed with a pharmaceutically acceptable carrier.
Yet another aspect of the invention provides a product containing a 5-HT2C receptor agonist and a 5-HT6 receptor antagonist as a combined preparation for simultaneous, separate or sequential use in therapy of a disease, in particular obesity, related to the 5-HT2C receptor and the 5-HT6 receptor.